This project explores basic etiologic and pathogenetic mechanisms in congenital heart disease, through the study of strains of dogs having hereditary lesion-specific defects in cardiovascular development. Breeding experiments are aimed at estimating the proportion of phenotypic variance in each defect due to the additive effects of genes (heritability). Possible synergism of genes predisposing to congenital heart disease with known cardiac teratogens will be investigated. The malformations to be studied are: patent ductus arteriosus (PDA), pulmonic stenosis, fibrous ring subaortic stenosis, and conus septum defects (including ventricular septal defects and tetralogy of Fallot). The pathogenesis of each defect will be studied by retrograde embryologic analysis, utilizing serial sectioning and wax plate reconstruction of the heart at critical stages of development. The possible pathogenetic roles of abnormalities in cell proliferation and synthesis of mucopolysaccharides will be investigated by organ culture and autoradiographic techniques. Correlated physiologic and anatomic studies of the ductus arteriosus in hereditary PDA include determination of the response of the isolated perfused ductus to variations in PO2 and varying concentrations of acetylcholine and norepinephrine. The pathogenesis of left heart failure and pulmonary hypertension in pups with hereditary PDA, and the pathogenesis of coronary arterial and myocardial lesions in subaortic stenosis will be studied by hemodynamic and anatomic methods.